Loderbauer, Lisa and Knaup, Karl X. and Reisenbüchler, Daniel and Kaiser, Nicolas and Naas, Stephanie and Schneider, Karen and Wopperer, Florian J. and Wiesener, Antje and Pasutto, Francesca and Schiffer, Mario and Daniel, Christoph and Broeker, Katharina A. E. and Merhof, Dorit and Buettner-Herold, Maike and Wiesener, Michael S. (2026) Alport Syndrome is a Partial Tubulointerstitial Disease of the Kidney. KIDNEY INTERNATIONAL REPORTS, 11 (2): 103694. ISSN 2468-0249
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Introduction: Recent genetic studies have shown that Alport syndrome (AS) is much more prevalent than clinically recognized, suggesting that atypical cases may phenocopy other kidney diseases. To date, pathomechanistic studies of AS have focused exclusively on the glomerular membrane, yet equally strong expression of collagen a(IV) chains is found along the distal renal tubule. We hypothesized that genetically determined abnormality of the tubular collagen IV (a345) molecule contributes to kidney failure and may drive atypical phenotypes. Methods: Histology and primary tubular cells (PTCs) of 8 patients with AS were investigated alongside controls. Results: Collagen a5 (IV) was detected within the tubular basement membrane (BM) (TBM) of the distal segments of renal tubules by immunohistochemistry. In situ hybridization on human tissues and protein detection of collagen a5 (IV) in PTC cultures clearly showed that the distal tubular apparatus predominantly produces collagen IV for the TBM. Electron microscopy of biopsies from patients with AS demonstrated irregularities of the TBM, somewhat similar as described for the glomerular BM (GBM). Finally, computer-assisted analyses showed that in biopsies of patients with AS, interstitial fibrosis preferentially occurs in spatial vicinity of the affected distal tubules. Conclusion: Our study demonstrates that the collagen IV (a345) molecule within the TBM is largely produced by the distal tubule itself. In AS, the TBM shows ultrastructural changes, which may induce fibrotic molecular signatures, as tubulointerstitial fibrosis appears to start in the vicinity of the distal tubule. Therefore, we postulate that the progression of kidney disease in AS may in part stem from the (distal) tubular apparatus.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | GLOMERULAR-BASEMENT-MEMBRANE; IV COLLAGEN; RENAL-FUNCTION; TRIPLE-HELIX; EXPRESSION; MUTATIONS; FAILURE; ANTIGEN; GENE; extracellular matrix; hearing impairment; hereditary nephritis; microhematuria; proteinuria; thin basement |
| Subjects: | 000 Computer science, information & general works > 004 Computer science 500 Science > 570 Life sciences |
| Divisions: | Biology, Preclinical Medicine > Institut für Physiologie Informatics and Data Science > Department Computational Life Science > Chair of Image Analysis and Computer Vision (Prof. Dr.-Ing. Dorit Merhof) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 23 Jun 2026 06:38 |
| Last Modified: | 23 Jun 2026 06:38 |
| URI: | https://pred.uni-regensburg.de/id/eprint/66923 |
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